Cai S X, Zhou Z L, Huang J C, Whittemore E R, Egbuwoku Z O, Hawkinson J E, Woodward R M, Weber E, Keana J F
CoCensys, Inc., Irvine, California 92618, USA.
J Med Chem. 1996 Nov 8;39(23):4682-6. doi: 10.1021/jm960520y.
A series of 4-hydroxy-3-nitroquinolin-2(1H)-ones (HNQs) was synthesized by nitration of the corresponding 2,4-quinolinediols. The HNQs were evaluated as antagonists at the glycine site of NMDA receptors by inhibition of [3H]DCKA binding to rat brain membranes. Selected HNQs were also tested for functional antagonism by electrophysiological assays in Xenopus oocytes expressing either 1a/2C subunits of NMDA receptors or rat brain AMPA receptors. The structure-activity relationships (SAR) of HNQs showed that substitutions in the 5-, 6-, and 7-positions in general increase potency while substitutions in the 8-position cause a sharp reduction in potency. Among the HNQs tested, 5,6,7-trichloro HNQ (8i) was the most potent antagonist with an IC50 of 220 nM in [3H]DCKA binding assay and a Kb of 79 nM from electrophysiological assays. Measured under steady-state conditions HNQ 8i is 240-fold selective for NMDA over AMPA receptors. The SAR of HNQs was compared with those of 1,4-dihydroquinoxaline-2,3-diones (QXs) and 1,2,3,4-tetrahydroquinoline-2,3,4-trione 3-oximes (QTOs). In general, HNQs have similar potencies to QXs with the same benzene ring substitution pattern but are about 10 times less active than the corresponding QTOs. HNQs are more selective for NMDA receptors than the corresponding QXs and QTOs. The similarity of the SAR of HNQs, QXs, and QTOs suggested that these three classes of antagonists might bind to the glycine site in a similar manner. With appropriate substitutions, HNQs represent a new class of potent and highly selective NMDA receptor glycine site antagonists.
通过相应的2,4 - 喹啉二醇的硝化反应合成了一系列4 - 羟基 - 3 - 硝基喹啉 - 2(1H) - 酮（HNQ）。通过抑制[³H]DCKA与大鼠脑膜的结合，评估了HNQ作为N - 甲基 - D - 天冬氨酸（NMDA）受体甘氨酸位点拮抗剂的活性。还通过电生理测定法，在表达NMDA受体1a/2C亚基或大鼠脑α - 氨基 - 3 - 羟基 - 5 - 甲基 - 4 - 异恶唑丙酸（AMPA）受体的非洲爪蟾卵母细胞中，对选定的HNQ进行了功能性拮抗测试。HNQ的构效关系（SAR）表明，5、6和7位的取代通常会增强活性，而8位的取代会导致活性急剧降低。在所测试的HNQ中，5,6,7 - 三氯HNQ（8i）是最有效的拮抗剂，在[³H]DCKA结合试验中的IC50为220 nM，电生理试验中的Kb为79 nM。在稳态条件下测量，HNQ 8i对NMDA受体的选择性是对AMPA受体的240倍。将HNQ的SAR与1,4 - 二氢喹喔啉 - 2,3 - 二酮（QX）和1,2,3,4 - 四氢喹啉 - 2,3,4 - 三酮3 - 肟（QTO）的SAR进行了比较。一般来说，具有相同苯环取代模式的HNQ与QX具有相似的活性，但活性比相应的QTO低约10倍。HNQ对NMDA受体的选择性高于相应的QX和QTO。HNQ、QX和QTO的SAR相似性表明，这三类拮抗剂可能以相似的方式与甘氨酸位点结合。通过适当的取代，HNQ代表了一类新型的强效且高度选择性的NMDA受体甘氨酸位点拮抗剂。
